: Rett Syndrome (RTT) is one of the Autism Spectrum Disorders (ASDs) with a known genetic cause and represents one of the leading causes of mental retardation in females. RTT is caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). The onset of RTT after normal early postnatal development and the precipitous loss of learned language and motor skills suggest a hypothesis that the clinical features of RTT result from a failure of activity-dependent neuronal development. Recently we discovered that MeCP2 suppresses Brain Derived Neurotrophic Factor (BDNF) expression in the absence of neuronal stimuli. In the presence of stimuli, MeCP2 undergoes CaMKII-mediated phosphorylation and releases repression to Bdnf. We have characterized a phosphorylation site (S421) on MeCP2 that selectively senses neuronal activity to control Bdnf transcription, modulate dendritic outgrowth and spine maturation. Our findings challenged the canonical view of MeCP2 as a global transcriptional represser and implicated MeCP2 in the molecular program controlling experience-dependent neuronal development. However, it is not clear how phosphorylation of S421 controls the function of MeCP2. In addition, developing an animal model where activity-dependent phosphorylation of MeCP2 is disrupted will provide the ultimate tool to address the role of MeCP2 in neuronal development. Thus, we plan to use biochemical, genetic, imaging, and molecular biology techniques to address two specific aims: 1) To characterize the molecular mechanisms underlying activity-dependent regulation of gene expression by MeCP2. 2) To test the in vivo contribution of activity dependent MeCP2 phosphorylation for nervous system function by generation of a MeCP2 S421A knock-in mouse model. We will initiate our aims during the mentored phase and I will carry on the characterization during the independent phase of this award. I plan to establish an independent research program focused on the biology of neurological diseases such as RTT and ASDs in the near future. It is our hope that the proposed experiments will provide a better understanding of MeCP2 function, give insight into the mechanisms of activity-dependent gene expression and neuronal development, and provide new opportunities for the development of therapeutic strategies to alleviate RTT pathology. ?
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